1. PRINCIPLES OF BIOCHEMISTRY
LEHNINGER
PRINCIPLES OF BIOCHEMISTRY
CHAPTER 21
Lipid Biosynthesis

2. Lipid: triacylgycerol, phospholipid, cholesterol
Synthesis and break down occur by different pathways, are catalyzed by different enzymes, and take place in different parts of cells
Three carbon intermediate, malonyl-CoA, is required for lipid biosynthesis

3. Malonyl-CoA is formed form acetyl-CoA and bicarbonate
Acetyl-CoA carboxylase has three functional regions
biotin carrier protein
biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction
Transcarboxylase, which transfers activated CO2 from biotin to acetyl-CoA, producing malonyl-CoA
The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site
FIGURE 21-1 The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction (see Figure 16-16); and transcarboxylase, which transfers activated CO2 (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.

4. Fatty acid assembled in a repeating four-step sequence catalyzed by fatty acid synthase
FIGURE 21-2 Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to illustrate the role of decarboxylation in facilitating condensation. The β-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of β oxidation, but in the reverse sequence: 2 the β-keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group.

5. FAS II found in plants and bacteria and is dissociated system
FAS I: found in vertebrates, consist of a single multifunctional polypeptide chain; seven active sites for different reactions lie in separate domains
b-ketoacyl-ACP synthase (KS), malonyl/acetyl-CoA—ACP transferase (MAT),
b-hydroxyacyl-ACP dehydratase (DH), enoyl-ACP reductase (ER),
b-ketoacyl-ACP reductase (KR),
acyl carrier protein (ACP)
TE is a thioesterase that releases the palmitate product from ACP when the synthesis is complete
FIGURE 21-3a The structure of fatty acid synthase type I systems. The low-resolution structures of (a) the mammalian (porcine; derived from PDB ID 2CF2) and (b) fungal enzyme systems (derived from PDB IDs 2UV9, 2UVA, 2UVB, and 2UVC) are shown. (a) All of the active sites in the mammalian system are located in different domains within a single large polypeptide chain. The different enzymatic activites are: β-ketoacyl-ACP synthase (KS), malonyl/acetyl-CoA—ACP transferase (MAT), β-hydroxyacyl-ACP dehydratase (DH), enoyl-ACP reductase (ER), and β-ketoacyl-ACP reductase (KR). ACP is the acyl carrier protein. The linear arrangement of the domains in the polypeptide is shown in the lower panel. The seventh domain (TE) is a thioesterase that releases the palmitate product from ACP when the synthesis is completed. The ACP and TE domains are disordered in the crystal and are therefore not shown in the structure.
FAS II found in plants and bacteria and is dissociated system

6. The overall process of palmitate synthesis
Single products (palmitate), no intermediates are released. 2 carbons from acetyl-CoA and the rest of the carbon from acetyl-CoA via malonyl-CoA
FIGURE 21-4 The overall process of palmitate synthesis. The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO2 at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of four, then six, then eight carbons, and so on. The final product is palmitate (16:0).

7. Throughout the process of fatty acid synthesis, the intermediates remain covalently attached as thioester to one of two thiol group; KS or ACP
Acyl carrier protein (ACP). The prosthetic group is 4′-phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP
FIGURE 21-5 Acyl carrier protein (ACP). The prosthetic group is 4′-phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis.

8. FIGURE 21-6 Sequence of events during synthesis of a fatty acid
FIGURE 21-6 Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

9. 7acetyl-CoA + 7CO2 + 7ATP  7 malonyl-CoA + 7ADP + 7Pi
Seven cycles of condensation and reduction produce the 16-carbon saturated palmitoyl group, stop elongation, is released from ACP
7acetyl-CoA + 7CO2 + 7ATP  7 malonyl-CoA + 7ADP + 7Pi
Acetyl-CoA + 7 malonyl-CoA + 14 NADPH +14H+  Palmitate + 7CO2 + 8Co-A + 14NADP+ + 6H2O
Overall,
8acetyl-CoA + 7ATP + 14 NADPH + 14H+  Palmitate + 7ADP + 7Pi + 8Co-A + 14NADP+ + 6H2O
FIGURE 21-7 Beginning of the second round of the fatty acid synthesis cycle. The butyryl group is on the Cys —SH group. The incoming malonyl group is first attached to the phosphopantetheine ﾑSH group. Then, in the condensation step, the entire butyryl group on the Cys —SH is exchanged for the carboxyl group of the malonyl residue, which is lost as CO2 (green). This step is analogous to step 1 in Figure The product, a six-carbon β-ketoacyl group, now contains four carbons derived from malonyl-CoA and two derived from the acetyl-CoA that started the reaction. The β-ketoacyl group then undergoes steps 2 through 4, as in Figure 21-6.

10. Subcellular localization of lipid metabolism
FIGURE 21-8 Subcellular localization of lipid metabolism. Yeast and vertebrate cells differ from higher plant cells in the compartmentation of lipid metabolism. Fatty acid synthesis takes place in the compartment in which NADPH is available for reductive synthesis (i.e., where the [NADPH]/[NADP+] ratio is high); this is the cytosol in animals and yeast, and the chloroplast in plants. Processes in red type are covered in this chapter.
Fatty acid synthesis takes place in the compartment in which NADPH is available for reductive synthesis. The [NADH]/[NAD+] ratio is much smaller, so the NAD+-dependent oxidative catabolism of glucose take place in cytosol. In mitochondria, high [NADH]/[NAD+] ratio favors the reduction of oxygen

11. Production of NADPH
FIGURE 21-9 Production of NADPH. Two routes to NADPH, catalyzed by (a) malic enzyme and (b) the pentose phosphate pathway.

12. In the photosynthetic cell, fatty acid synthesis occurs in chloroplast stroma, because NADPH is produced by light reaction

13. Shuttle for transfer of acetyl groups from mitochondria to the cytosol
Two ATP is consumed
Half of NADPH is from malic enzyme reaction
Half is from PPP
FIGURE Shuttle for transfer of acetyl groups from mitochondria to the cytosol. The mitochondrial outer membrane is freely permeable to all these compounds. Pyruvate derived from amino acid catabolism in the mitochondrial matrix, or from glucose by glycolysis in the cytosol, is converted to acetyl-CoA in the matrix. Acetyl groups pass out of the mitochondrion as citrate; in the cytosol they are delivered as acetyl-CoA for fatty acid synthesis. Oxaloacetate is reduced to malate, which can return to the mitochondrial matrix and is converted to oxaloacetate. The major fate for cytosolic malate is oxidation by malic enzyme to generate cytosolic NADPH; the pyruvate produced returns to the mitochondrial matrix.
All the acetyl-CoA used is formed in mitochondria from PA oxidation and from the catabolism of the aa. Thus shuttle system is required. Acetyl-CoA from fatty acid oxidation is not a significant source of fatty acid synthesis because the two pathway are reciprocally regulated

14. Regulation of fatty acid synthesis
Acetyl-CoA carboxylase reaction is a rate limiting step in fa biosynthesis
palmitoyl-CoA: allosteric inhibitor (feedback inhibition)
citrate (ATP and acetyl-CoA high in mitochondria): allosteric activator
phosphorylation inhibits
dephosphorylation (polymerization) activates
FIGURE Regulation of fatty acid synthesis. (a) In the cells of vertebrates, both allosteric regulation and hormone-dependent covalent modification influence the flow of precursors into malonyl-CoA. In plants, acetyl-CoA carboxylase is activated by the changes in [Mg2+] and pH that accompany illumination (not shown here). (b) Filaments of acetyl-CoA carboxylase (the active, dephosphorylated form) as seen with the electron microscope.
In plants, acetyl-CoA carboxylase is activated by the changes in [Mg2+] and pH increase that accompany illumination
Fatty acid oxidation and synthesis do not occur simultaneously
 Malonyl-CoA inhibits carnitine acyltransferase I and then shuts downs fa oxidation

15. Routes of synthesis of other fatty acids
Palmitate is the precursor of stearate and longer-chain saturated fa, monounsaturated acids palmitoleate and oleate in SER
Mammals cannot synthesize linoleate or a-linolenate (essential fa)
FIGURE Routes of synthesis of other fatty acids. Palmitate is the precursor of stearate and longer-chain saturated fatty acids, as well as the monounsaturated acids palmitoleate and oleate. Mammals cannot convert oleate to linoleate or α-linolenate (shaded pink), which are therefore required in the diet as essential fatty acids. Conversion of linoleate to other polyunsaturated fatty acids and eicosanoids is outlined. Unsaturated fatty acids are symbolized by indicating the number of carbons and the number and position of the double bonds, as in Table 10-1.

16. The fa and NADPH simultaneously undergo two electron oxidation
Unsaturation reaction is catalyzed by fatty acyl-CoA desaturase, a mixed function oxidase in smooth ER
The fa and NADPH simultaneously undergo two electron oxidation
FIGURE Electron transfer in the desaturation of fatty acids in vertebrates. Blue arrows show the path of electrons as two substrates—a fatty acyl–CoA and NADPH—undergo oxidation by molecular oxygen. These reactions take place on the lumenal face of the smooth ER. A similar pathway, but with different electron carriers, occurs in plants.

17. Oxygenase: catalyzed oxidative reactions in which oxygen atoms are directly incorporated into to the substrate molecule, forming a new hydroxyl or carboxyl group
Dioxygenase: both oxygen atom are incorporated into the organic molecule

18. Monooxygenase catalyzed only one oxygen is incorporated into the organic substrate and the other being reduced to H2O
Called hydroxylase or mixed-function oxidase or mixed-function oxygenase
Tyrosine hydroxylase, cytochrome P450

19. Eicosanoids are from 20-carbon poylunsaturated fatty acid
Eicosanoids are a family of very potent biological signaling molecule
In response hormonal or other stimuli, phospholipase A2 induces the release of arachidonic acid from membrane
Arachidonic acid converts into PGH2 by cyclooxygenase (COX)
COX-1 regulates the secretion of gastric mucin
COX-2 mediates inflammation, pain and fever
Thus, pain can be relieved by inhibiting COX-2
FIGURE 21-15a The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes. (a) After arachidonate is released from phospholipids by the action of phospholipase A2, the cyclooxygenase and peroxidase activities of COX (also called prostaglandin H2 synthase) catalyze the production of PGH2, the precursor of other prostaglandins and thromboxanes.

20. Aspirin is irreversible inhibitor
NSAID, nonsteroidal antiinflammatory drug
Thromboxane induce constriction of blood vessels and platelet aggregation
Low doses of aspirin reduce the probability of hear attacks and strokes by reducing thromboxane production
FIGURE 21-15b The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes. (b) Aspirin inhibits the first reaction by acetylating an essential Ser residue on the enzyme. Ibuprofen and naproxen inhibit the same step, probably by mimicking the structure of the substrate or an intermediate in the reaction.

21. COX-2 specific cyclooxygenase inhibitors used as pain relievers
FIGURE 21-15c The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes. (c) COX-2–specific cyclooxygenase inhibitors used as pain relievers (see text).
COX-2 specific cyclooxygenase inhibitors used as pain relievers

22. The linear pathway from arachidonate to leukotrienes
FIGURE The "linear" pathway from arachidonate to leukotrienes.

23. Biosynthesis of phosphatidic acid
Incorporation into triacylglycerol or into phospholipid component
Both pathways begin with the formation of fatty acyl ester of glycerol
Glycerol-3-P is derived from DHAP and glycerol
Fatty acyl-CoA by acyl-CoA synthetase
Diacylglycerol-3-P (phosphatidic acid)
FIGURE Biosynthesis of phosphatidic acid. A fatty acyl group is activated by formation of the fatty acyl-CoA, then transferred to ester linkage with L-glycerol 3-phosphate, formed in either of the two ways shown. Phosphatidic acid is shown here with the correct stereochemistry at C-2 of the glycerol molecule. To conserve space in subsequent figures (and in Figure 21-14), both fatty acyl groups of glycerophospholipids, and all three acyl groups of triacylglycerols, are shown projecting to the right.

24. Phosphatidic acid is precursor of both triacylglycerol and glycerophospholipid
FIGURE Phosphatidic acid in lipid biosynthesis. Phosphatidic acid is the precursor of both triacylglycerols and glycerophospholipids. The mechanisms for head-group attachment in phospholipid synthesis are described later in this section.

25. Regulation of triacylglycerol synthesis by insulin
FIGURE Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin; in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness (p. 929).
Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin. In uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production
People in severe ketosis smell acetone, so the condition is mistaken for drunkenness

26. An additional factor in the balance between biosynthesis and degradation of fa is that approximately 75% of all fatty acids released by lipolysis are reesterified to form triacylglycerol rather than used for fuel by triacylglycerol cycle
The level of free fatty acids in blood reflects both the rate of released fa and the balance between the synthesis and breakdown of TAG in adipose tissue and liver
FIGURE The triacylglycerol cycle. In mammals, triacylglycerol molecules are broken down and resynthesized in a triacylglycerol cycle during starvation. Some of the fatty acids released by lipolysis of triacylglycerol in adipose tissue pass into the bloodstream, and the remainder are used for resynthesis of triacylglycerol. Some of the fatty acids released into the blood are used for energy (in muscle, for example), and some are taken up by the liver and used in triacylglycerol synthesis. The triacylglycerol formed in the liver is transported in the blood back to adipose tissue, where the fatty acid is released by extracellular lipoprotein lipase, taken up by adipocytes, and reesterified into triacylglycerol.

27. Adipose tissue generates G3P by glyceroneogenesis
FIGURE Glyceroneogenesis. The pathway is essentially an abbreviated version of gluconeogenesis, from pyruvate to dihydroxyacetone phosphate (DHAP), followed by conversion of DHAP to glycerol 3-phosphate, which is used for the synthesis of triacylglycerol.
Glyceroneogenesis has multiple roles
In adipose tissue, it controls the rate of FA released to blood

28. Flux through the triacylglycerol cycle between liver and adipose tissue is controlled by PEPCK activity
Glucocorticoid hormone regulate the level of PEPCK reciprocally in the liver and adipose tissue

29. Glucocorticoid hormones
stimulate glyceroneogenesis and gluconeogenesis in the liver
suppress glyceroneogenesis in the adipose tissue
by reciprocal regulation of the gene expressing PEPCK in the two tissues
FIGURE 21-22a Regulation of glyceroneogenesis. (a) Glucocorticoid hormones stimulate glyceroneogenesis and gluconeogenesis in the liver, while suppressing glyceroneogenesis in the adipose tissue (by reciprocal regulation of the gene expressing PEP carboxykinase (PEPCK) in the two tissues); this increases the flux through the triacylglycerol cycle. The glycerol freed by the breakdown of triacylglycerol in adipose tissue is released to the blood and transported to the liver, where it is primarily converted to glucose, although some is converted to glycerol 3-phosphate by glycerol kinase.

30. High levels of free fatty acids in blood interfere with glucose utilization in muscle and promote the insulin resistance that leads to type2 diabetes
Thiazolidinediones reduce the levels of fatty acid in the blood and increase sensitivity to insulin

31. Thiazolidinediones activate a nuclear receptor, peroxisome proliferator-activated receptor g (PPARg), which induces the activity of PEPCK
They increase the rate of glyceroneogenesis, thus increasing the resynthesis of triacylglycerol in adipose tissue and reducing the amount of free fatty acid in the blood
FIGURE Regulation of glyceroneogenesis. (b) A class of drugs called thiazolidinediones are now used to treat type 2 diabetes. In this disease, high levels of free fatty acids in the blood interfere with glucose utilization in muscle and promote insulin resistance. Thiazolidinediones activate a nuclear receptor called peroxisome proliferator-activated receptor γ (PPARγ), which induces the activity of PEP carboxykinase. Therapeutically, thiazolidinediones increase the rate of glyceroneogenesis, thus increasing the resynthesis of triacylglycerol in adipose tissue and reducing the amount of free fatty acid in the blood.

32. Biosynthesis of membrane phospholipids
synthesis of the backbone molecule
attachment of fatty acid to backbone through ester or amide linkage
attachment of hydrophilic head group through phosphodiester linkage
modification of head group
FIGURE Head-group attachment. The phospholipid head group is attached to a diacylglycerol by a phosphodiester bond, formed when phosphoric acid condenses with two alcohols, eliminating two molecules of H2O.

33. Two general strategies for forming PDE bond of phospholipids
FIGURE Two general strategies for forming the phosphodiester bond of phospholipids. In both cases, CDP supplies the phosphate group of the phosphodiester bond.

34. Phospholipid synthesis in E. Coli employs CDP-diacylglycerol
FIGURE Origin of the polar head groups of phospholipids in E. coli. Initially, a head group (either serine or glycerol 3-phosphate) is attached via a CDP-diacylglycerol intermediate (strategy 1 in Figure 21-24). For phospholipids other than phosphatidylserine, the head group is further modified, as shown here. In the enzyme names, PG represents phosphatidylglycerol; PS, phosphatidylserine.
Phospholipid synthesis in E. Coli employs CDP-diacylglycerol

35. Eukaryotes synthesize anionic phospholipids from CDP-diacylglycerol
FIGURE Synthesis of cardiolipin and phosphatidylinositol in eukaryotes. These glycerophospholipids are synthesized using strategy 1 in Figure Phosphatidylglycerol is synthesized as in bacteria (see Figure 21-25). PI represents phosphatidylinositol.

36. The major path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotes
FIGURE The major path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotes. AdoMet is S-adenosylmethionine; adoHcy, S-adenosylhomocysteine.

37. Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals
FIGURE 21-28a Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals. (a) Phosphatidylserine is synthesized by Ca2+-dependent head-group exchange reactions promoted by phosphatidylserine synthase 1 (PSS1) or phosphatidylserine synthase 2 (PSS2). PSS1 can use either phosphatidylethanolamine or phosphatidylcholine as a substrate. The pathways used by bacteria and yeast correspond to those shown in Figure

38. Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals
FIGURE 21-28b Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals. (b) The same strategy shown here for phosphatidylcholine synthesis (strategy 2 in Figure 21-24) is also used for salvaging ethanolamine in phosphatidylethanolamine synthesis.

39. Synthesis of ether lipids and plasmalogens
FIGURE Synthesis of ether lipids and plasmalogens. The newly formed ether linkage is shaded pink. The intermediate 1-alkyl-2-acylglycerol 3-phosphate is the ether analog of phosphatidic acid. Mechanisms for attaching head groups to ether lipids are essentially the same as for their ester-linked analogs. The characteristic double bond of plasmalogens (shaded blue) is introduced in a final step by a mixed-function oxidase system similar to that shown in Figure

40. Biosynthesis of sphingolipids
Synthesis of sphinganine from palmitoyl-CoA and Ser
Attachment of fatty acid in amide linkage to yield N-acylsphinganine
Desaturation to N-acylshphingosine (ceramide)
Attachment of head group to sphingolipid such as sphingomyelin or cerebroside
FIGURE Biosynthesis of sphingolipids. Condensation of palmitoyl-CoA and serine (forming β-ketosphinganine) followed by reduction with NADPH yields sphinganine, which is then acylated to N-acylsphinganine (a ceramide). In animals, a double bond (shaded pink) is created by a mixed-function oxidase before the final addition of a head group: phosphatidylcholine, to form sphingomyelin, or glucose, to form a cerebroside.

41. FIGURE 21-32 Origin of the carbon atoms of cholesterol
FIGURE Origin of the carbon atoms of cholesterol. This can be deduced from tracer experiments with acetate labeled in the methyl carbon (black) or the carboxyl carbon (red). The individual rings in the fused-ring system are designated A through D.
Origin of the carbon atoms of cholesterol. This can be deduced from tracer experiments with acetate labeled in the methyl carbon (black) or the carboxyl carbon (red). The individual rings in the fused-ring system are designated A through D

42. FIGURE 21-33 Summary of cholesterol biosynthesis
FIGURE Summary of cholesterol biosynthesis. The four stages are discussed in the text. Isoprene units in squalene are set off by red dashed lines.

43. FIGURE 21-34 Formation of mevalonate from acetyl-CoA
FIGURE Formation of mevalonate from acetyl-CoA. The origin of C-1 and C-2 of mevalonate from acetyl-CoA is shown in pink.

44. FIGURE 21-35 Conversion of mevalonate to activated isoprene units
FIGURE Conversion of mevalonate to activated isoprene units. Six of these activated units combine to form squalene (see Figure 21-36). The leaving groups of 3-phospho-5-pyrophosphomevalonate are shaded pink. The bracketed intermediate is hypothetical.

45. FIGURE 21-36 Formation of squalene
FIGURE Formation of squalene. This 30-carbon structure arises through successive condensations of activated isoprene (five-carbon) units.

46. FIGURE Ring closure converts linear squalene to the condensed steroid nucleus. The first step in this sequence is catalyzed by a mixed-function oxidase (a monooxygenase), for which the cosubstrate is NADPH. The product is an epoxide, which in the next step is cyclized to the steroid nucleus. The final product of these reactions in animal cells is cholesterol; in other organisms, slightly different sterols are produced, as shown.
Ring closure converts linear squalene to the condensed steroid nucleus

47. Cholesterol has several fates
Synthesis in vertebrates takes place in the liver
Export in biliary cholesterol, bile acid, cholesteryl ester
Membrane synthesis or a precursor for steroid hormone and vitamin D
They are carried in the blood plasma as plasma lipoprotein
Different combinations of lipids and proteins produce particles of different densities, ranging from chylomicrons to high-density lipoproteins
TABLE 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties

48. FIGURE Lipoproteins. (a) Structure of a low-density lipoprotein (LDL). Apolipoprotein B-100 (apoB-100) is one of the largest single polypeptide chains known, with 4,636 amino acid residues (Mr 513,000). One particle of LDL contains a core with about 1,500 molecules of cholesteryl esters, surrounded by a shell composed of about 500 more molecules of cholesterol, 800 molecules of phospholipids, and one molecule of apoB-100.
Structure of a low-density lipoprotein. Apolipoprotein B-100 is one of the largest single polypeptide chains. One particle of LDL contains a core with about 1,500 molecules of cholesteryl esters, surrounded by a shell composed of about 500 more molecules of cholesterol, 800 molecules of phospholipids, and one molecule of apoB-100

49. Chylomicrons: least dense and largest lipoproteins, composed of TAG, apoB-48, apoA-I and apoA-II. transport products from dietary fat digestion to peripheral tissues
VLDL: main source of TAG exported from liver to muscle and adipose tissues. apoB-100 is an essential component
LDL: consists of cholesterol, apoB-100 molecule. cholesterol carrier, delivering cholesterol to liver and peripheral tissues, receptor mediated uptake
HDL: originate in the liver and small intestine as small, protein-rich particle
LCAT (lecithin—cholesterol acyltransferase) on the surface of nascent HDL partice converts the cholesterol and VLDL remnants to cholesteryl ester, begin to form a core. This mature HDL return to the liver, where cholesterol is unload.
FIGURE 21-39b Lipoproteins. (b) Four classes of lipoproteins, visualized in the electron microscope after negative staining. Clockwise from top left: chylomicrons, 50 to 200 nm in diameter; VLDL, 28 to 70 nm; HDL, 8 to 11 nm; and LDL, 20 to 25 nm. For properties of lipoproteins, see Table 21-1.

50. FIGURE 21-40a Lipoproteins and lipid transport
FIGURE 21-40a Lipoproteins and lipid transport. (a) Lipids are transported in the bloodstream as lipoproteins, which exist as several variants that have different functions, different protein and lipid compositions (see Tables 21-1, 21-2), and thus different densities. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries. Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL. Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually converts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver. The liver takes up LDL, VLDL remnants (called intermediate density lipoprotein, or IDL), and chylomicron remnants by receptormediated endocytosis. Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts.

51. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries
Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL.
Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually converts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver
The liver takes up LDL, VLDL remnants (called intermediate density lipoprotein, or IDL), and chylomicron remnants by receptor mediated endocytosis
Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts
FIGURE 21-40a Lipoproteins and lipid transport. (a) Lipids are transported in the bloodstream as lipoproteins, which exist as several variants that have different functions, different protein and lipid compositions (see Tables 21-1, 21-2), and thus different densities. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries. Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL. Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually converts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver. The liver takes up LDL, VLDL remnants (called intermediate density lipoprotein, or IDL), and chylomicron remnants by receptormediated endocytosis. Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts.

52. Uptake of cholesterol by receptor-mediated endocytosis
FIGURE Uptake of cholesterol by receptor-mediated endocytosis.

53. Cholesterol biosynthesis is regulated at several levels
Cholesterol production is regulated by intracellular cholesterol concentration and by glucagon and insulin
Rate limiting step is HMG-CoA to mevalonate by HMG-CoA reductase
Transcriptional regulation of HMG-CoA reductase
Sterol regulatory element-binding proteins (SREBP)
When cholesterol high, SREBP is secured in ER
Low, SREBP is cleaved by protease and enter nucleus, leading to activate target genes
FIGURE SREBP activation. Sterol regulatory element-binding proteins (SREBPs, shown in green) are embedded in the ER when first synthesized, in a complex with the protein SREBP cleavage-activating protein (SCAP, red). (N and C represent the amino and carboxyl termini of the proteins.) When bound to SCAP, SREBPs are inactive. When sterol levels decline, the complex migrates to the Golgi complex, and SREBP is cleaved by two different proteases in succession. The liberated amino-terminal domain of SREBP migrates to the nucleus, where it activates transcription of sterol-regulated genes.

54. Hormonal regulation is mediated by covalent modification of HMG-CoA reductase
Glucagon stimulate phosphorylation (inactivation) and insulin promotes dephosphorylation, activating the enzyme and favoring cholesterol synthesis
Cholesterol activate ACAT and represses expression of LDL receptor, reducing the uptake of LDL from blood
FIGURE Regulation of cholesterol formation balances synthesis with dietary uptake. Glucagon promotes phosphorylation (inactivation) of HMG-CoA reductase; insulin promotes dephosphorylation (activation). X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase.

55. BOX 21-3 FIGURE 1 Statins as inhibitors of HMG-CoA reductase
BOX 21-3 FIGURE 1 Statins as inhibitors of HMG-CoA reductase. A comparison of the structures of mevalonate and four pharmaceutical compounds (statins) that inhibit HMG-CoA reductase.
Statins as inhibitors of HMG-CoA reductase

56. FIGURE 21-45 Some steroid hormones derived from cholesterol
FIGURE Some steroid hormones derived from cholesterol. The structures of some of these compounds are shown in Figure

57. FIGURE 21-47 Overview of isoprenoid biosynthesis
FIGURE Overview of isoprenoid biosynthesis. The structures of most of the end products shown here are given in Chapter 10.